In our earlier studies we have contributed to, and validated, the development of operationalized diagnostic criteria for severe premenstrual dysphoria. Additionally, we have developed experimental models for the triggering of symptoms in both premenstrual dysphoric disorder and postpartum depression that we continue to employ in our efforts to identify both the underlying biology of these conditions as well as the development of new safe and effective therapies for women with these conditions.[unreadable] As a continuation of these studies, we have demonstrated that women with PMD who respond to GnRH agonist-induced ovarian suppression experience a recurrence of PMD after the initial re-exposure to combined estradiol and progesterone (but not placebo); however, recurrent symptoms do not occur once hormone levels are stabilized over the subsequent two months of replacement therapy. These observations are of both theoretical and practical importance, as they both identify promising phenotypes and suggest the physiologic basis for the susceptibility to experience PMD but will also provide alternative hormone-based therapies for women with this condition.[unreadable] Our studies of cognitive function in women with PMD demonstrate impaired emotional coding and recognition, increased susceptibility to affective interference, and decreased capacity for emotional reappraisal and recovery in women with PMD compared with controls (as identified by the administration of the Cambridge Neuropsychological Test Automated Battery and the Emotional Processing Battery). Additionally, a suite of statistical descriptors were identified to have very high sensitivity and specificity for PMD compared with recurrent brief depression and controls by applying chaos-based Approximate Entropy modeling to mood rating data.[unreadable] In addition to our studies on the behavioral effects of changes in sex steroids across the menstrual cycle and during the postpartum, we have employed a number of methodologies to investigate the underlying biological mechanisms of these conditions including studies investigating the hypothalamic-pituitary-adrenal (HPA) axis (i.e., stress response) as well as studies employing multimodal neuroimaging such as positron emission tomography (PET), structural magnetic resonance imaging (MRI), and functional magnetic resonance imaging (fMRI). Our preliminary studies of the stress axis suggest that women with PMD have increased corticotrophin-(CRH) stimulated ACTH secretion independent of hormone condition compared with asymptomatic controls. Our neuroimaging protocols have demonstrated for the first time a differential reward-related pattern of brain activation in the orbital frontal cortex and the amygdala during the luteal compared with the follicular phase of the menstrual cycle using fMRI technology. Additionally, PET studies employing the radioligand for the serotonin transporter protein, DASB, have demonstrated lower binding potential during the luteal phase of the menstrual cycle relative to the follicular phase in several brain regions including the midbrain, pons, insula, and posterior cingulate cortices. Menstrual cycle-related changes in gray matter volume (measured by voxel-based morphometric analyses on high-resolution structural MRI ) have been observed in areas of the brain regulating mood and affective adaptation including the following: subgenual cingulate cortex (increased), and in an area slightly inferior to the left amygdala (decreased) during the follicular phase compared with the luteal phase of the menstrual cycle in women. Finally, sex differences in reward-related brain activation were observed using fMRI with men activating the ventral striatum bilaterally more than women during anticipation of uncertain rewards, and women activating the anterior medial prefrontal cortex more than men at the time of reward delivery.[unreadable] Our efforts to identify markers of vulnerability to the development of PMD have identified the following findings: 1) Four single nucleotide polymorphisms in the estrogen receptor alpha gene positively associated with the disorder, and evidence for epistasis with the COMT gene. This is the first demonstration of an association between a polymorphic genetic variant and PMD. 2) The absence of an increased prevalence of postpartum depression (relative to community-based samples) in women with prospectively confirmed PMD.[unreadable] Our therapeutic clinical trials have demonstrated the following: 1) The five alpha reductase inhibitor, dutasteride, a medication that inhibits neurosteroid synthesis has no effect on either the symptoms of PMD or the LH surge prior to ovulation. 2) We have documented for the first time the hourly change in symptom ratings in women with PMD after successful treatment with the selective serotonin reuptake inhibitor fluoxetine. In most women, therapeutic response occurs within 48 to 72 hours, far sooner than is typically observed in the treatment of depression with the same medications, the response is similar to the change in PMD symptoms surrounding the onset of menses, and is associated with a reduced diurnal variability in affective symptoms in these women. 3) The absence of historical or biological measures predictive of a therapeutic response to GnRH agonist-induced ovarian suppression in women with PMD. Finally, preliminary results demonstrate the acute short-term efficacy of estradiol therapy in women with postpartum depression under placebo-controlled conditions.